Asymmetrically modified boron hydride type compound and a method for producing an optically active alcohol derivative by the use thereof

ABSTRACT

The present invention relates to an asymmetrically modified borohydride type compound obtained by reacting an optically active amino alcohol represented by the formula, ##STR1## or its salt with an acid with a borohydride compound; its production method; and a method for producing an optically active alcohol derivative useful as fungicides, herbicides or plant growth regulators and represented by the formula, ##STR2## which comprises asymmetrically reducing a ketone compound represented by the formula, ##STR3## with the asymmetrically modified borohydride type compound.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application is a division of application Ser. No. 781,453, filedSept. 30, 1985, now U.S. Pat. No. 4,760,149, which in turn is acontinuation-in-part of application Ser. No. 688,287, filed Jan. 7, 1985(now abandoned), which in turn is a continuation-in-part of applicationSer. No. 674,924, filed Nov. 21, 1984 (now abandoned) which applicationSer. No. 674,924 is the U.S. National Stage based on PCT/JP/00161, filedApr. 3, 1984.

TECHNICAL FIELD

The present invention relates to a novel asymmetrically modified boronhydride type compound, its production and a method for producing anoptically active alcohol derivative using the compound. Moreparticularly, it relates to an asymmetrically modified boron hydridetype compound obtained by reacting an optically active amino alcoholrepresented by the formula (I), ##STR4## wherein R₁ represents an aryl,alkyl, cycloalkyl or aralkyl group, R₂ represents an aryl, alkyl,aralkyl or alkoxycarbonyl group, R₃ represents a hydrogen atom or analkyl or aralkyl group, and a mark * means an asymmetric carbon, or itssalt with an acid, with a boron hydride compound; its production method;and a method for producing an optically active alcohol derivativerepresented by the formula (III), ##STR5## wherein R₄ represents analkyl, cycloalkyl or cycloalkenyl group, or a phenyl group which may besubstituted with a halogen atom or an alkyl, haloalkyl, cyano, alkoxyl,phenoxy or phenyl group, R₅ represents an imidazol-1-yl or1,2,4-triazol-1-yl group, R₆ represents a tert-butyl group, or a1,1-dimethyl-2-phenylethyl group wherein benzene ring may be substitutedwith a halogen atom, and a mark * has the same meaning as above, bycarrying out the asymmetric reduction of a ketone compound representedby the formula (II), ##STR6## wherein R₄, R₅ and R₆ have the samemeanings as above, with said asymmetrically modified boron hydride typecompound.

BACKGROUND ART

The alcohol derivative represented by the above formula (III), i.e. anazole type α,β-unsaturated alcohol derivative is known to be useful asan active ingredient for fungicides, plant growth regulators orherbicides, as represented for example by1-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-ol,1-(4-chlorophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-ol and1-cyclohexyl-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-ol [JapanesePatent Application Kokai (Laid-open) Nos. 124771/1980, 100547/1979 and111477/1980]. And, it is also well known that there is a remarkabledifference in the activity between the optical isomers, and that, forexample, with reference to the foregoing1-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-oland1-(4-chlorophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-ol,the (-)-isomer has a strong activity as fungicides, while the (+)-isomerhas a strong activity as plant growth regulators and herbicides[Japanese Patent Application Kokai (Laid-open) Nos. 99575/1982 and106669/1982].

For this reason, there is a great demand for the development of a methodto produce either one of the (-)- or (+)-optical isomer according tointended uses and yet with a good efficiency in industry.

As the conventionally well-known common reducing agent for reducing thecarbonyl group of ketone compounds into alcohol compounds, there arevarious reagents represented by lithium aluminum hydride and sodiumborohydride. The reduction product produced when these reagents are usedis an optically inactive, i.e. racemic compound, and when these reagentsare used for the reduction of ketone compounds having an unsaturatedbond, particularly α,β-conjugated unsaturated ketones like the materialused in the method of the present invention, reduction of the doublebond in addition to the carbonyl group is easy to occur, and besidesthere also comes out a possibility that the steric configurationcorrelated with the double bond is isomerized.

As the conventionally employed method for producing optically activealcohol derivatives by asymmetric reduction, there are the followingmethods to carry out the asymmetric reduction of ketone compounds withlithium aluminum hydride modified with an optically active compound: Amethod of using an optically active N-methylephedrine [I. Jacquet, etal., Tetrahedron Letters, 1974, 2065; J. P. Vigneron, et al.,Tetrahedron, 32, 939 (1976); J. P. Vigneron, et al., TetrahedronLetters, 1979, 2683; idem, ibid., 1980, 1735; and Japanese PatentApplication Kokai (Laid-open) Nos. 99575/1982 and 106669/1982]; a methodof using an optically active proline derivative [M. Asami, et al.,Heterocycles, 12, 499 (1979)] and a method of using an optically activebinaphthyl derivative [R. Noyori, et al., J. Am. Chem. Soc., 101, 3129(1979); R. Noyori, et al., ibid., 101, 5843 (1979)].

These methods, however, may not always be said to be satisfactory inindustry, for example, in the following points: (1) Since lithiumaluminum hydride is used, there is a danger such as ignition by contactwith moisture, and (2) in order to obtain an alcohol compound having ahigher optical purity, additives such as N-substituted aniline arerequired in large amounts.

Also, in asymmetric reduction, the following methods are reported as amethod for producing optically active alcohols using an asymmetricallymodified boron hydride-reducing agent:

1 A method of using sodium borohydride and the onium salt of opticallyactive ephedrine [described in S. Colona, et al., J. Chem. Soc., PerkinTrans I, 371 (1978)],

2 a method of using an optically active amine-borane complex [describedin R. F. Borch, et al., J. Org. Chem. 37, 2347 (1972)],

3 a method of using an α-amino acid ester-borane complex [described inM. F. Grundon, et al., Tetrahedron Letters, 295 (1976)], and

4 a method of the asymmetric reduction of aromatic ketones with anoptically active amino alcohol and borane [described in A. Hirao, etal., J. Chem. Soc., Chem. Comm., 315 (1981); S. Itsuno, et al., ibid.,469 (1983); and S. Itsuno et al., J. Chem. Soc. Perkin Trans I, 1673(1983)].

But, the methods 1, 2 and 3 are too low in optical yield to say thatthey are a practical method. Also, the method 4 may not always be saidto be satisfactory to carry it out in industry because, in order toattain high optical purity, borane of two times by mole, as converted toboron basis, as much as amino alcohol is required.

DISCLOSURE OF INVENTION

In view of the situation like this, the present inventors extensivelystudied a method for obtaining the optically active alcohol derivativerepresented by the formula (III) by the asymmetric reduction of theketone compound represented by the above formula (II), and as a result,found that, by using an asymmetrically modified boron hydride compound(hereinafter referred to as present compound) obtained by reacting theoptically active amino alcohol represented by the above formula (I) orits salt with an acid with a boron hydride compound, only the carbonylgroup is selectively reduced into the objective optically active alcoholderivative with safety as well as good efficiency.

Next, the present invention will be illustrated.

In the optically active amino alcohol represented by the above formula(I), a material for the present compound, specific examples of asubstituent R₁ include a C₁ -C₁₀ alkyl, C₅ -C₁₀ cycloalkyl and C₇ -C₁₆aralkyl groups, a phenyl group which may be substituted with a halogenatom or an alkyl, cyano, alkoxyl or alkoxycarbonyl group, and a naphthylgroup which may be substituted with a halogen atom or an alkyl, cyano,alkoxyl or alkoxycarbonyl group. Specific examples of R₂ include a C₆-C₁₆ aryl, C₁ -C₁₀ alkyl and C₇ -C₁₆ aralkyl groups and analkyloxycarbonyl group in which the number of carbon atoms constitutingthe alkyl group is 1 to 10. Specific examples of R₃ include a hydrogenatom, a C₁ -C₆ alkyl and C₇ -C₁₆ aralkyl groups. More specifically, asthe optically active amino alcohol represented by the formula (I), theremay be given norephedrine, norpseudoephedrine, threonine ester,1,2-diphenyl-2-amino-1-ethanol,1-(2,5-dimethylphenyl)-2-amino-1-propanol and1-α-naphthyl-2-amino-1-propanol. These optically active amino alcoholsare produced, for example, by the methods described in M. J. Kalm, J.Org. Chem., 25, 1929-37 (1960); W. H. Hartung, et al., J. Am. Chem.Soc., 52, 3317-22 (1930); W. H. Hartung, et al., J. Am. Chem. Soc., 51,2262-6 (1929); M. C. Kloetzel, et al., J. Org. Chem., 11, 390-4 (1946),and the like.

In the present invention, the halogen atom represents fluorine atom,chlorine atom or bromine atom.

Next, reference will be made to a method for producing the presentcompound.

The present compound, when the boron hydride compound is a metalborohydride, is obtained by reacting a salt, as obtained from theoptically active amino alcohol represented by the formula (I) and anacid, with the metal borohydride in a solvent, or when the borohydridecompound is a borane, it is obtained by directly reacting the opticallyactive amino alcohol represented by the formula (I) with the borane in asolvent. As the foregoing acid which is a material for producing thesalt of the optically active amino alcohol, there are given mineralacids (e.g. hydrochloric acid, sulfuric acid, nitric acid, phosphoricacid, carboxylic acids (e.g. acetic acid), organic sulfonic acids (e.g.p-toluenesulfonic acid) and the like. Said salt may be used as such ormay be produced, in situ, from the optically active amino alcohol andthe acid in the reaction system for producing the present reducingagent.

As the metal borohydride described above, there are given for examplesodium borohydride, potassium borohydride, lithium borohydride, zincborohydride, etc. Generally, however, the object of the presentinvention can sufficiently be achieved by using easily available sodiumborohydride. As the borane, for example diborane, borane-tetrahydrofurancomplex, borane-dimethyl sulfide complex, etc. may be given.

In production of the present compound, the molar ratio of theborohydride compound to the optically active amino alcohol is, when saidcompound is a metal borohydride, 0.7:1 to 2:1, preferably 0.7:1 to1.3:1, more preferably 1 to 1, as converted to boron basis, and whensaid compound is a borane, said molar ratio is 0.7:1 to 1.3:1,preferably 1 to 1.

The solvent used in producing the present compound is not particularlylimited, so long as it does not take part in the reaction. For example,however, there are given aromatic hydrocarbons (e.g. benzene, toluene,xylene, chlorobenzene), halogenated hydrocarbons (e.g. methylenechloride, 1,2-dichloroethane, chloroform, carbon tetrachloride), andmixtures thereof. When the metal borohydride is used, in order to solveit, for example dimethyl sulfoxide, diglyme, dimethylformamide,1,3-dimethyl-2-imidazolidinone or the like may be used in combination.The reaction temperature is generally within a range of -78° to 100° C.,preferably -40° to 100° C. The reaction is generally carried out in aninert gas atmosphere such as nitrogen, argon, etc.

Also, by decomposing the present compound with an aqueous alkalisolution, a compound represented by the formula (V), ##STR7## whereinR₁, R₂, R₃ and a mark * have the same meanings as above, is obtained.

The present compound thus obtained may be used for the subsequentreduction after separated from the reaction solution, but generally, itis used as the solution without being separated therefrom.

Next, reference will be made to a method for producing the opticallyactive alcohol derivative of the above formula (III) by reduction of theketone compound represented by the above formula (II) using the presentcompound thus obtained.

The amount of the present compound used in the reduction is not lessthan 0.5 mole, generally within a range of 1 to 5 moles, as converted toboron basis, based on 1 mole of the ketone compound represented by theformula (II), and even the range of 1 to 2 moles can sufficientlyachieve the object.

Also, the solvent used in the foregoing reduction is not particularlylimited, so long as it is an inactive solvent. Preferably, however,organic solvents such as aromatic hydrocarbons (e.g. benzene, toluene,xylene, chlorobenzene), halogenated hydrocarbons (e.g. methylenechloride, 1,2-dichloroethane, chloroform, carbon tetrachloride), ethers(e.g. diethyl ether, tetrahydrofuran, dioxane, diglyme) and mixturesthereof are used. Also, the solvent used in producing the presentcompound may be used as it is or in mixture with the solvents describedabove. The reduction is generally carried out in an inert gas atmosphereas described above. The temperature of the reduction is generally withina range of -30° to 100° C., and industrially within a range of -10° to50° C.

The foregoing reduction may be carried out in the presence of an acid,and particularly when sodium borohydride is used as a material for thepresent compound, isomerization between the E form and Z form of theketone compound represented by the above formula (I) is inhibited,whereby the yield of the objective optically active alcohol derivativecan be increased. As the acid, there are given for example Lewis acids(e.g. titanium tetrachloride, boron trifluoride etherate, aluminumchloride), carboxylic acids (e.g. acetic acid, chloroacetic acid,propionic acid) and mineral acids (e.g. hydrochloric acid, sulfuricacid, phosphoric acid). The molar ratio of these acids to the ketonecompound is generally within a range of 0.01:1 to 1:1, preferably 0.01:1to 0.5:1.

After the reduction is carried out in this way, the aqueous solution ofa mineral acid (e.g. hydrochloric acid, sulfuric acid) is generallyadded to the reaction solution, the organic layer is separated from theaqueous layer, washed with water and dried, and then the organic solventis removed by evaporation. By this procedure, the objectiveaforementioned optically active alcohol derivative represented by theformula (III) is obtained in a high yield.

The optical purity is obtained by measuring the optical rotation of theproduct obtained, or directly measuring the enantiomer ratio byhigh-performance liquid chromatography with optically active packingmaterials.

Hereupon, the optically active amino alcohol used can easily berecovered, with its steric configuration maintained, by adding anaqueous alkali solution to the aqueous layer after the reaction andextracting with an organic solvent. The recovered optically active aminoalcohol can be re-used.

BEST MODE FOR CARRYING OUT THE INVENTION EXAMPLE 1

In a nitrogen atmosphere, 0.338 g of (+)-norephedrine hydrochloride wassuspended in 5 ml of deutero chloroform, and after cooling to -30° C., asolution of 0.0681 g of sodium borohydride in 1 ml of dimethylformamidewas added. On raising the temperature of the resulting mixture from -30°C. to room temperature over 2 hours, 87 ml of hydrogen gas was generatedto obtain a solution of the present compound. ¹¹ B nuclear magneticresonance spectrum (standard, BF₃.OEt₂) of this solution was as follows:-20.95 ppm, +7.21 ppm.

Thereafter, this solution was decomposed with 2.5N aqueous sodiumhydroxide solution, and the organic layer was washed with water andpurified by column chromatography on silica gel with a n-hexane/ethylacetate (1:1) mixture as a developing solvent to obtain 0.112 g of acrystal.

¹¹ B nuclear magnetic resonance spectrum (standard, BF₃.OEt₂): -20.5ppm.

M.p. 93°-95° C. (dec.).

This crystal, as a result of X-ray diffraction analysis, was identifiedto be a borohydride compound having the following structure: ##STR8##[α]_(D) +49.7° (c=1.0, THF).

EXAMPLE 2

Reaction was carried out in the same manner as in Example 1 except thatdimethylformamide was replaced by deutero dimethylformamide, to obtain asolution of the present compound having the following physical property:

¹ H nuclear magnetic resonance spectrum [CDCl₃ -DMF-d₇, δ(ppm)]:0.97(d), 1.04(d), 2.75-3.15(m), 3.1-3.5(broad), 4.2-4.7(broad), 5.18(d),7.31(s).

EXAMPLES 3 AND 4

Reaction was carried out in the same manner as in Example 2 except that(+)-norephedrine hydrochloride was replaced by(+)-1-(2,5-dimethylphenyl)-2-amino-1-propanol hydrochloride and(-)-1-α-naphthyl-2-amino-1-propanol hydrochloride, to obtain a solutionof the present compound having the physical property shown in Table 1.

                  TABLE 1                                                         ______________________________________                                        Example No. .sup.11 B NMR spectrum [δ (ppm)]                            ______________________________________                                        3           -20.6, +6.5                                                       4           -20.3, +6.4                                                       ______________________________________                                    

EXAMPLE 5

In a nitrogen atmosphere, a solution of 0.272 g (1.8 mmoles) of(+)-norephedrine in 4 ml of 1,2-dichloroethane was added dropwise at-78° C. to a solution comprising 1.8 ml (0.9 mmole) of a 0.50Mdiborane-tetrahydrofuran solution and 2 ml of 1,2-dichloroethane, andthe temperature of the resulting mixture was raised from -78° C. to roomtemperature over about 2 hours. ¹¹ B nuclear magnetic resonance spectrumof this solution was as follows: -20.7 ppm, +7.7 ppm.

EXAMPLE 6

In a nitrogen atmosphere, 0.338 g (1.8 mmoles) of (+)-norephedrinehydrochloride was suspended in 5 ml of 1,2-dichloroethane, and aftercooling to -30° C., a solution of 0.0681 g (1.8 mmoles) of sodiumborohydride in 1 ml of dimethylformamide was added. On raising thetemperature of the resulting suspension from -30° C. to room temperatureover 2 hours, 87 ml of hydrogen gas was generated. Thereafter, asolution of 0.39 g (1.2 mmoles) of(E)-1-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-one(E/Z=99.9/0.1) in 4 ml of 1,2-dichloroethane was added to thissuspension at room temperature, and then stirring was carried out for 23hours. Thereafter, 6 ml of 2M hydrochloric acid was added, followed bystirring for 2 hours. The organic layer was washed with water, dried andconcentrated under reduced pressure. The residue was purified on acolumn packed with 2 g of silica gel with a chloroform solvent and thenconcentrated under reduced pressure to obtain 0.39 g of(-)-(E)-1-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-olas a crude crystal. By gas-chromatographic analysis, it was found thatthe conversion was 96.4%, and the composition of the reaction productwas: E-form alcohol, 98.3% and Z-form alcohol, 1.7% (Z-form alcohol wasproduced through isomerization of the ketone compound to the Z-form,followed by reduction of the carbonyl group).

Optical rotation [α]_(D) : -19.93° (c=1.0, CHCl₃).

By high-performance liquid-chromatographic analysis using an opticallyactive column, it was found that the enantiomer ratio of the E-formalcohol was: (-)-isomer, 85.1% and (+)-isomer, 14.9%. The optical yieldwas 70.2%.

EXAMPLES 7 TO 10

Reaction was carried out according to Example 6 using the reactionsolvents described below in place of 1,2-dichloroethane, to obtain(-)-(E)-1-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-ol.

The results are shown in Table 2. In the table, the solvents inparentheses in the column, "Reaction solvent", are a solvent used fordissolving sodium borohydride.

                                      TABLE 2                                     __________________________________________________________________________                          Reaction       Optical                                               Reduc-   product Enantiomer                                                                           yield of                                              tion                                                                              Conver-                                                                            E-form                                                                            Z-form                                                                            ratio (-/+)                                                                          E-form                                   Example                                                                            Reaction                                                                              time                                                                              sion alcohol                                                                           alcohol                                                                           of E-form                                                                            alcohol                                  No.  solvent (hr)                                                                              (%)  (%) (%) alcohol                                                                              (%)                                      __________________________________________________________________________    7    1,2-Dichloro-                                                                         25  94.9 98.8                                                                              1.2 83.5/16.5                                                                            67                                            ethane                                                                        (diglyme)                                                                8    1,2-Dichloro-                                                                         43  93.7 97.0                                                                              3.0 80/20  60                                            ethane                                                                        (dimethyl                                                                     sulfoxide)                                                               9    Toluene 25  97.4 96.8                                                                              3.2 78/22  56                                            (dimethyl-                                                                    formamide)                                                               10   Chlorobenzene                                                                         72  99.9 97.1                                                                              2.9 80.5/19.5                                                                            61                                            (dimethyl-                                                                    formamide)                                                               __________________________________________________________________________

EXAMPLES 11 TO 13

Reaction was carried out according to Example 6 using(E)-1-(4-chlorophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-one(E/Z=99.8/0.2) in place of(E)-1-(2,4-dichlorophenyl-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-oneand at varying molar ratios, 1.0, 1.1 and 1.2, of sodium borohydride tonorephedrine hydrochloride. The results are shown in Table 3. Hereuponthe saturated alcohol of the reaction products means a product obtainedby hydrogenation of both the carbonyl group and the carbon/carbon doublebond contained in the ketone compound which is a material.

                                      TABLE 3                                     __________________________________________________________________________    Molar                                                                         ratio of                                                                      sodium boro-         Reaction product   Optical                                    hydride to                                                                           Reac-        Satu-   Enantiomer                                                                           yield of                                   norephedrine                                                                         tion                                                                              Conver-                                                                            E-form                                                                            rated                                                                             Z-form                                                                            ratio (-/+)                                                                          E-form                                Example                                                                            hydro- time                                                                              sion alcohol                                                                           alcohol                                                                           alcohol                                                                           of E-form                                                                            alcohol                               No.  chloride                                                                             (hr)                                                                              (%)  (%) (%) (%) alcohol                                                                              (%)                                   __________________________________________________________________________    11   1.0    24.0                                                                              97.5 83.7                                                                               0.4                                                                              15.9                                                                              81.1/18.9                                                                            62.2                                  12   1.1    67.5                                                                              99.9 79.3                                                                               1.4                                                                              19.2                                                                              82.3/17.7                                                                            64.6                                  13   1.2    15.5                                                                              96.7 64.1                                                                              13.8                                                                              22.1                                                                              83.5/16.5                                                                            67.0                                  __________________________________________________________________________

EXAMPLES 14 AND 15

In a nitrogen atmosphere, a solution of 1.8 mmoles of the following eachacid in 1 ml of 1,2-dichloroethane was added to a solution of 0.272 g(1.8 mmoles) of (+)-norephedrine in 4 ml of 1,2-dichloroethane, andafter cooling to -30° C., a solution of 0.0681 g (1.8 mmoles) of sodiumborohydride in 1 ml of dimethylformamide was added. The temperature ofthe resulting mixture was raised from -30° C. to room temperature over 2hours to prepare the present compound. Thereafter, asymmetric reductionof the ketone compound was carried out in the same manner as in Example6. The results are shown in Table 4.

                                      TABLE 4                                     __________________________________________________________________________                     Reaction product   Optical                                                        Satu-   Enantiomer                                                                           yield of                                              Conver-                                                                            E-form                                                                            rated                                                                             Z-form                                                                            ratio (-/+)                                                                          E-form                                    Example     sion alcohol                                                                           alcohol                                                                           alcohol                                                                           of E-form                                                                            alcohol                                   No.  Acid   (%)  (%) (%) (%) alcohol                                                                              (%)                                       __________________________________________________________________________    14   Acetic acid                                                                          92.8 98.5                                                                              1.0 0.5 81.5/18.5                                                                            63                                        15   p-Toluene-                                                                           91.8 94.7                                                                              --  5.3 72/28  44                                             sulfonic acid                                                                 monohydrate                                                              __________________________________________________________________________

EXAMPLE 16

Reaction was carried out on a scale of ten times that of Example 6. In anitrogen atmosphere, a solution of 0.681 g (0.018 mole) of sodiumborohydride in 9.44 g of dimethylformamide was added dropwise at -20° C.to a suspension of 3.38 g (0.018 mole) of (+)-norephedrine hydrochloridein 62.8 g of 1,2-dichloroethane, and the temperature of the resultingmixture was raised from -20° C. to room temperature over 2 hours.Thereafter, a solution of 3.89 g (0.012 mole) of(E)-1-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-one(E/Z=97.6/2.4) in 50.24 g of 1,2-dichloroethane was added, and stirringwas carried out at room temperature for 21 hours and then at 40° C. for3 hours. The reaction solution was decomposed with addition of 7.22 g of10% hydrochloric acid and 2.1 g of water, and the organic layer wasseparated, washed with water and concentrated under reduced pressure toobtain 3.89 g of(-)-(E)-1-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-olas a crystal. The conversion of 99.9%, and the composition of theproduct obtained was: E-form alcohol, 95.8%; saturated alcohol, 0.2%;Z-form alcohol, 3.5%; and others, 0.5%. The enantiomer ratio of theE-form alcohol was: (-)-isomer, 85.2% and (+)-isomer, 14.8%. The opticalyield was 70.4%.

EXAMPLE 17

Reaction was carried out in the same manner as in Example 16 except thatthe amounts of 1,2-dichloroethane, a solvent, used were reduced to 13.52g and 12.2 g from 62.8 g and 50.24 g, respectively. The conversion was99.9%, and the composition of the product obtained was: E-form alcohol,88.9%; saturated alcohol, 0.9%; Z-form alcohol, 9.4%; and others, 0.8%.The enantiomer ratio of the E-form alcohol was: (-)-isomer, 84.1% and(+)-isomer, 15.9%. The optical yield was 68.2%.

EXAMPLES 18 TO 24

Asymmetric reduction of each of(E)-1-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-one(E/Z=97.6/2.4) and(E)-1-(4-chlorophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-one(E/Z=98.9/1.1) was carried out according to Example 6 using thehydrochloride of each optically active aminc alcohol described below inplace of (+)-norephedrine hydrochloride. The results are shown in Table5.

    TABLE 5      Reaction  Reaction product Enantiomer ratio Optical yield Example     Optically active time Conversion E-form Saturated Z-form (-/+) of E-form o     f E-form No. Ketone compound amino alcohol (hr) (%) alcohol (%) alcohol     (%) alcohol (%) alcohol alcohol (%)                 18      ##STR9##      ##STR10##      69 98.7 93.6 <0.1 6.3 95.9/4.1  91.8      19 "     ##STR11##      50 88.4 92.4 <0.1 7.5 10.6/89.4 78.8      20     ##STR12##      ##STR13##      69 99.9 96.6 <0.1 3.3 90.2/9.8  80.4      21     ##STR14##      ##STR15##      50 97.8 96.1 <0.1 3.8 11.0/89.0 78.0      22 "     ##STR16##      24 85.0 94.7 -- 5.3 23.5/76.5 53.0      23 "     ##STR17##      24 97.1 97.2  1.4 1.4 66.5/33.5 33.0      24 "     ##STR18##      24 53.6 89.6      1.1 9.3 31.7/68.3 36.6

EXAMPLES 25 TO 29

Reaction was carried out in the same manner as in Example 6 except thatthe (E) and (Z) forms of1-cyclohexyl-4,4-dimethyl-2-(1,2,4-triazol-1-yl)-1-penten-3-one (the E/Zratios of the former and the latter were 99.9/0.1 and 0.1/99.9,respectively) were used in place of(E)-1-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-one,and that the hydrochlorides of the optically active amino alcohols andthe solvents (solvents in parentheses are a solvent used for dissolvingsodium borohydride) described below were used. The results are shown inTable 6.

                                      TABLE 6                                     __________________________________________________________________________                                                 Reaction product                                                                   Enantiomer                                                                          Optical                                                                 ratio                                                                               yield of              Example                                                                            Ketone                                                                              Optically active            Conversion                                                                          Alcohol                                                                            of E-form                                                                           E-form                No.  compound                                                                            amino alcohol    Solvent    (%)   E/Z  alcohol                                                                             alcohol               __________________________________________________________________________                                                            (%)                   25   E-form                                                                               ##STR19##       1,2-Dichloroethane (dimethylformamide)                                                   100   97.1/2.9                                                                           80.9/19.1                                                                           61.8                  26   E-form                                                                               ##STR20##       Chloroform (dimethylformamide)                                                           100   97.6/2.4                                                                           17.7/82.3                                                                           64.6                  27   E-form                                                                               ##STR21##       1,2-Dichloroethane (dimethylformamide)                                                   99.5  94.9/5.1                                                                           20.3/79.7                                                                           59.4                  28   Z-form                                                                               ##STR22##       1,2-Dichloroethane (dimethylformamide)                                                   100   2.0/98.0                                                                           -10.7° (1)                                                                   --                    29   Z-form                                                                               ##STR23##       1,2-Dichloroethane (dimethylformamide)                                                   100    1.2/98.8                                                                           +9.9° (1)                                                                   --                    __________________________________________________________________________     (1) Specific rotation of the product (c = 1.0, CHCl.sub.3)               

EXAMPLE 30

In a nitrogen atmosphere, 0.338 g (1.8 mmoles) of (+)-norephedrinehydrochloride was suspended in 5 ml of 1,2-dichloroethane, and to thissuspension was added at -30° C. a solution of 0.0681 g (1.8 mmoles) ofsodium borohydride in 1 ml of dimethylformamide. The temperature of theresulting suspension was raised to room temperature over 2 hours.Thereafter, to this suspension was added at room temperature a solutionof 0.0108 g (0.18 mmole) of acetic acid and 0.35 g (1.2 mmoles) of(E)-1-(4-chlorophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-one(E/Z=99.8/0.2) in 4 ml of 1,2-dichloroethane. The subsequent treatmentwas carried out according to Example 6.

The conversion was 79.4%, and the composition of the product obtainedwas: E-form alcohol, 92.5%; saturated alcohol, 0.3%; and Z-form alcohol,7.2%. The enantiomer ratio of the E-form alcohol was: (-)-isomer, 76.1%and (+)-isomer, 23.9%. The optical yield was 52.2%.

EXAMPLES 31 TO 38

Reaction was carried out according to Example 30 using titaniumtetrachloride, boron trifluoride etherate, monochloroacetic acid,propionic acid and conc. sulfuric acid in place of acetic acid. Theresults are shown in Table 7.

                                      TABLE 7                                     __________________________________________________________________________    Lewis acid, carboxylic acid or mineral acid                                                                 Reaction                                        Example       Amount                                                                             Molar ratio (%) of                                                                       time Conversion                                 No.  Name     (g)  acid to amino alcohol                                                                    (hr) (%)                                        __________________________________________________________________________    31   Titanium 0.017                                                                              5          24   63.7                                            tetrachloride                                                            32   Titanium 0.009                                                                              2.5        24   84.4                                            tetrachloride                                                            33   Boron trifluoride                                                                      0.128                                                                              50         23   51.1                                            etherate                                                                 34   Boron trifluoride                                                                      0.026                                                                              10         24   87.7                                            etherate                                                                 35   Monochloroacetic                                                                       0.017                                                                              10         21   68.3                                            acid                                                                     36   Propionic acid                                                                         0.013                                                                              10         68   89.1                                       37   Conc. sulfuric                                                                         0.018                                                                              10         69   92.4                                            acid                                                                     38   Conc. sulfuric                                                                         0.009                                                                              5          24   83.2                                            acid                                                                     __________________________________________________________________________                            Enantiomer                                            Reaction product        ratio (-/+)                                                                           Optical yield                                 E-form  Saturated                                                                             Z-form  of E-form                                                                             of E-form                                     alcohol (%)                                                                           alcohol (%)                                                                           alcohol (%)                                                                           alcohol alcohol (%)                                   __________________________________________________________________________    96.6    0.3     3.1     66.3/33.7                                                                             32.6                                          92.6    0.1     7.3     76.8/23.2                                                                             53.6                                          98.5    0.6     0.9     64.2/36.8                                                                             28.4                                          87.6    0.2     12.2    81.3/18.7                                                                             62.6                                          91.2    0.3     8.5     69.3/30.7                                                                             38.6                                          89.1    --      10.9    67.6/32.4                                                                             35.2                                          90.2    --      9.8     74.3/25.7                                                                             48.6                                          89.8    --      10.2    79.2/20.8                                                                             58.4                                          __________________________________________________________________________

EXAMPLES 39 TO 41

Reaction was carried out according to Example 30 using varying molarratios of sodium borohydride to norephedrine hydrochloride. The resultsare shown in Table 8.

                  TABLE 8                                                         ______________________________________                                                           Molar ratio (%)                                                   Molar ratio (%)                                                                           of sodium   Reac-                                                 of acetic   borohydride to                                                                            tion  Conver-                                  Example                                                                              acid to amino                                                                             norephedrine                                                                              time  sion                                     No.    alcohol     hydrochloride                                                                             (hr)  (%)                                      ______________________________________                                        39     15          1.1         24    90.0                                     40     30          1.2         43    97.8                                      41*   15          1.1         24    97.2                                     ______________________________________                                                                      Optical                                         Reaction product  Enantiomer  yield of                                        E-form Saturated Z-form   ratio (-/+)                                                                             E-form                                    alcohol                                                                              alcohol   alcohol  of E-form alcohol                                   (%)    (%)       (%)      alcohol   (%)                                       ______________________________________                                        92.1   --         7.9     79.0/21.0 58.0                                      83.6   0.8       13.4     85.0/15.0 70.0                                      91.2   --         8.8     75.5/24.5 51.0                                      ______________________________________                                         *Chlorobenzene was used in place of 1,2dichloroethane.                   

EXAMPLE 42

In a nitrogen atmosphere, 0.393 g (0.0065 mole) of acetic acid was addedto a suspension of 8.18 g (0.0436 mole) of (-)-norephedrinehydrochloride in 62.17 g of chlorobenzene, and then a solution of 1.815g (0.0480 mole) of sodium borohydride in 9.35 g of dimethylformamide wasadded dropwise to this suspension at 5° to 10° C. for 1.5 hours.Thereafter, the resulting mixture was stirred at room temperature for 1hour, and then a solution of 8.42 g (0.0291 mole; E/Z=99.8/0.2) of(E)-1-(4-chlorophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-onein 49.7 g of chlorobenzene was added at room temperature. The resultingmixture was stirred at the same temperature for 18 hours. The reactionsolution was decomposed with addition of 17.50 g of 10% hydrochloricacid and 5 g of water, and the organic layer was separated, washed withwater and concentrated under reduced pressure to obtain 8.15 g(+)-(E)-1-(4-chlorophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-olas a crystal. The conversion was 99.8%, and the composition of theproduct obtained was: E-form alcohol, 90.8%; saturated alcohol, 2.3%;and Z-form alcohol, 6.9%. The enantiomer ratio of the E-form alcoholwas: (+)-isomer, 81.0% and (-)-isomer, 19.0%. The optical yield was62.0%.

EXAMPLE 43

In a nitrogen atmosphere, a solution of 2.64 g (0.0698 mole) of sodiumborohydride in 14.95 g of dimethylformamide was added dropwise at -20°C. to a suspension of 13.07 g (0.0696 mole) of (+)-norephedrinehydrochloride in 52.26 g of 1,2-dichloroethane, and the temperature ofthe resulting mixture was raised from -20° C. to room temperature over 2hours.

Thereafter, 0.35 g of phosphoric acid and then a solution of 16.12 g(0.0497 mole) of(E)-1-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-one(E/Z=97.6/2.4) in 49.37 g of 1,2-dichloroethane were added at 20° to 25°C., and stirring was carried out at the same temperature for 20 hours.The reaction solution was decomposed with addition of 24.17 g of 20%nitric acid and 4.6 g of water, and the organic layer was separated,washed with water and concentrated under reduced pressure to obtain15.60 g of(-)-(E)-1-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-olas a crystal. The conversion was 99.8%, and the composition of theproduct obtained was: E-form alcohol, 95.6%; saturated alcohol, 0.4%;Z-form alcohol, 3.2%; and others, 0.8%. The enantiomer ratio of theE-form alcohol was: (-)-isomer, 85.8% and (+)-isomer, 14.2%. The opticalyield was 71.6%.

EXAMPLE 44

In a nitrogen atmosphere, 0.338 g (1.8 mmoles) of (-)-norephedrinehydrochloride was suspended in a mixture comprising 15.4 μl (0.27 mmole)of acetic acid and 5 ml of 1,2-dichloroethane, and after cooling to -30°C., a solution of 0.0749 g (1.98 mmoles) of sodium borohydride in 1 mlof dimethylformamide was added. The temperature of the resultingsuspension was raised from -30° C. to room temperature over 2 hours.Thereafter, to this suspension was added at room temperature a solutionof 0.31 g (1.2 mmoles) of(E)-1-cyclohexyl-4,4-dimethyl-2-(1,2,4-triazol-1-yl)-1-penten-3-one(E/Z=99.9/0.1) and 10.3 μl (0.18 mmole) of acetic acid in1,2-dichloroethane, and stirring was carried out for 24 hours. Thesubsequent treatment was carried out in the same manner as in Example 6to obtain(-)-(E)-1-cyclohexyl-4,4-dimethyl-2-(1,2,4-triazol-1-yl)-1-penten-3-ol.The conversion was 100%, and the composition of the product obtainedwas: E-form alcohol, 97.4% and Z-form alcohol, 2.6%. The enantiomerratio of the E-form alcohol was: (-)-isomer, 77.7% and (+)-isomer,22.3%.

EXAMPLE 45

In a nitrogen atmosphere, a solution of 0.272 g of (+)-norephedrine in 4ml of 1,2-dichloroethane was added dropwise at -78° C. to a mixturecomprising 1.8 ml of a 0.500M diborane-tetrahydrofuran solution and 2 mlof 1,2-dichloroethane, and the temperature of the resulting mixture wasraised from -78° C. to room temperature over about 2 hours. Thereafter,to this solution was added dropwise at room temperature a solution of0.39 g of(E)-1-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-one(E/Z=99.9/0.1) in 4 ml of 1,2-dichloroethane, and stirring was carriedout for 24 hours. Thereafter, 6 ml of 2M hydrochloric acid was added tothe reaction solution, followed by stirring for about 2 hours. Theorganic layer was washed with water, dried over anhydrous sodium sulfateand concentrated under reduced pressure. The residue was purified on acolumn packed with 2 g of silica gel using a chloroform solvent and thenconcentrated under reduced pressure to obtain 0.39 g of(-)-(E)-1-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-olas a crude crystal. The conversion was 98.6%, and the composition of theproduct obtained was: E-form alcohol, 98.6% and Z-form alcohol, 1.4%.

Optical rotation [α]_(D) : -20.7° (c=1.0, CHCl₃).

Optical yield of E-form alcohol: 70%.

EXAMPLES 46 TO 50

Reaction was carried out according to Example 45 using the followingreaction solvents in place of 1,2-dichloroethane, to obtain(-)-(E)-1-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-ol.The results are shown in Table 9.

                                      TABLE 9                                     __________________________________________________________________________                           Reaction product                                                                       Optical                                                                            Optical                                                                  rotation                                                                           yield of                                             Reduction                                                                           Conver-       [α].sub.D                                                                    E-form                                   Example                                                                            Reaction                                                                             time  sion E-form alcohol/                                                                        (c = 1.0,                                                                          alcohol                                  No.  solvent                                                                              (hr)  (%)  Z-form alcohol                                                                         CHCl.sub.3)                                                                        (%)                                      __________________________________________________________________________    46   Ethyl ether                                                                          19    99.9 99.8/0.2 -16.18°                                                                     54                                       47   Dioxane                                                                              24    75.0 98.6/1.4 -14.40°                                                                     64                                       48   Toluene                                                                              21    99.5 99.4/0.6 -17.59°                                                                     59                                       49   Methylene                                                                            24    99.3 99.7/0.3 -20.50°                                                                     68                                            chloride                                                                 50   Carbon 23    81.0 99.7/0.3 -13.25°                                                                     55                                            tetrachloride                                                            __________________________________________________________________________

EXAMPLES 51 AND 52

Reaction was carried out in the same manner as in Example 45 except thattoluene was used as reaction solvent in place of 1,2-dichloroethane, thereaction time was changed to 23 hours, and that the molar ratio ofdiborane to (+)-norephedrine was varied, to obtain(-)-(E)-1-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-ol.The results are shown in Table 10.

                                      TABLE 10                                    __________________________________________________________________________                      Reaction product                                                                             Optical                                           Diborane/            Enantiomer                                                                           yield of                                          (+)-         E-form                                                                            Z-form                                                                            ratio (-/+)                                                                          E-form                                       Example                                                                            norephedrine                                                                         Conversion                                                                          alcohol                                                                           alcohol                                                                           of E-form                                                                            alcohol                                      No.  (molar ratio)                                                                        (%)   (%) (%) alcohol                                                                              (%)                                          __________________________________________________________________________    51   0.375/1.0                                                                            99.4  98.5                                                                              1.5 77/23  54                                           52   0.625/1.0                                                                            99.6  99.2                                                                              0.8 76/24  52                                           __________________________________________________________________________

EXAMPLES 53 TO 57

Reaction was carried out in the same manner as in Example 45 except thatthe optically active amino alcohols described below were used in placeof (+)-norephedrine, and that tetrahydrofuran and diethyl ether wereused as a reaction solvent. The results are shown in Table 11.

                                      TABLE 11                                    __________________________________________________________________________                               Reaction product                                                                             Optical                                  Optically    Reac-            Enantiomer                                                                           yield of                                 active       tion                                                                              Conver-                                                                            E-form                                                                            Z-form                                                                            ratio (-/+)                                                                          E-form                              Example                                                                            amino Reaction                                                                             time                                                                              sion alcohol                                                                           alcohol                                                                           of E-form                                                                            alcohol                             No.  alcohol                                                                             solvent                                                                              (hr)                                                                              (%)  (%) (%) alcohol                                                                              (%)                                 __________________________________________________________________________    53   L-    Tetrahydro-                                                                          117 88.6 99.9                                                                              0.1 35.4/64.4                                                                            29.2                                     threonine                                                                           furan                                                                   cyclohexyl                                                                    ester                                                                    54   L-    Diethyl                                                                              117 100  99.9                                                                              0.1 33.9/66.1                                                                            32.2                                     threonine                                                                           ether                                                                   cyclohexyl                                                                    ester                                                                    55   L-    Tetrahydro-                                                                           24 74.4 99.3                                                                              0.7 34.9/65.1                                                                            30.2                                     threonine                                                                           furan                                                                   ethyl                                                                         ester                                                                    56   L-    Diethyl                                                                               20 90.4 99.6                                                                              0.4 33.8/66.2                                                                            32.4                                     threonine                                                                           ether                                                                   ethyl                                                                         ester                                                                    57   (+)-1,2-                                                                            Tetrahydro-                                                                           24 83.9 98.2                                                                              1.8 68.0/32.0                                                                            36.0                                     Diphenyl-                                                                           furan                                                                   2-amino-                                                                      ethanol                                                                  __________________________________________________________________________

EXAMPLES 58 AND 59

Reaction was carried out in the same manner as in Example 45 except that(+)-norephedrine was replaced by (-)-norephedrine and(E)-1-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-one,and that the following ketone compounds were used. The results are shownin Table 12.

                                      TABLE 12                                    __________________________________________________________________________                              Reaction product                                                                           Enantiomer                                                                           Optical yield                                             E-form                                                                            Z-form                                                                            Saturated                                                                          ratio (-/+)                                                                          of E-form                       Example             Conversion                                                                          alcohol                                                                           alcohol                                                                           alcohol                                                                            of E-form                                                                            alcohol                         No.  Ketone compound                                                                              (%)   (%) (%) (%)  alcohol                                                                              (%)                             __________________________________________________________________________    58                                                                                  ##STR24##     97.6  96.3                                                                              3.1 0.6  15.1/84.9                                                                            69.8                                  ##STR25##                                                               59                                                                                  ##STR26##     100   99.0                                                                              1.0 --   73.9/26.1                                                                            47.8                                  ##STR27##                                                               __________________________________________________________________________

EXAMPLES 60 TO 69

Asymmetric reduction was carried out in the same manner as in Example 6,except that (+)-norephedrine hydrochloride was replaced by an aminoalcohol of (+)-2-amino-1-(2,5-dimethoxyphenyl)-1-propanol hydrochloride,(+)-2-amino-1-(2,5-diethoxyphenyl)-1-propanol hydrochloride,(-)-2-amino-1-(2,4-dimethoxyphenyl)-1-propanol hydrochloride,(+)-2-amino-1-(2-methoxyphenyl)-1-propanol hydrochloride or(-)-2-amino-1-(2-ethoxyphenyl)-1-propanol hydrochloride, toasymmetrically reduce a ketone compound of(E)-1-(4-chlorophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-one(E/Z=98.9/1.1),(E)-1-cyclohexyl-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-one(E/Z=99.9/0.1) or(E)-1-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-one(E/Z=97.6/2.4). The results are shown in Table 13.

    TABLE 13      Reaction product Enantiomer Optical yield    Reaction  E-form Saturated Z     -form ratio (-/+) of E-form Example   time Conversion alcohol alcohol     alcohol of E-form alcohol No. Ketone compound Amino alcohol (hr) (%) (%)     (%) (%) alcohol (%)                 60      ##STR28##      ##STR29##      24.0 99.9 95.0 <0.1 4.9 94.5/5.5  89.0    61.sup.(1) " " 98.0 94.2 96.2     <0.1 3.7 98.1/1.9  96.2      62     ##STR30##      " 23.0 100.0  97.2 -- 2.8 13.0/87.0 74.0      63 "     ##STR31##      20.0 100.0  97.3 -- 2.7 14.9/85.1 70.2      64     ##STR32##      ##STR33##      24.0 99.9 96.9 <0.1 3.0 94.7/5.3  89.4      65     ##STR34##      ##STR35##      24.0 99.9 96.6 <0.1 3.3 90.3/9.7  80.6      66 "     ##STR36##      26.0 97.8 95.7 <0.1 4.2 11.2/88.8 77.6      67     ##STR37##      ##STR38##      69.0 98.2 90.5 <0.1 9.4 97.3/2.7  94.6      68     ##STR39##      " 69.0 100.0  96.2 <0.1 3.7 96.6/3.4  93.2      69 "     ##STR40##      21.0 99.0 96.4 <0.1 3.5     .sup.(1) Reaction temperature is in the range of 10°-12° C.     instead of room temperature in Example 6.

EXAMPLE 70

Under a nitrogen atmosphere, 0.4459 g (1.8 mmoles) of(-)-erythro-2-amino-1-(2,4-dimethoxyphenyl)-1-propanol hydrochloride(optical purity, 98.6%) was suspended in 5 ml of 1,2-dichloroethane, thesuspension was cooled to -25° C., and after adding a solution of 0.0681g (1.8 mmoles) of sodium borohydride in 1 ml of dimethylformamide, thetemperature was raised from -25° C. to room temperature over 2.5 hours.Thereafter, to this suspension was added at 20° C. a solution of 0.35 g(1.2 mmoles) of(E)-1-(4-chlorophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-one(E/Z=98.9/1.1) in 4 ml of 1,2-dichloroethane, and the mixture wasstirred for 26 hours. Thereafter, decomposition was carried out at 45°C. with stirring with addition of 8 ml of 10% hydrochloric acid. Theorganic layer was washed with water, dried over anhydrous sodium sulfateand concentrated under reduced pressure to obtain 0.35 g of a crudecrystal of(+)-(E)-1-(4-chlorophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-ol.Gas chromatographic analysis showed that the conversion was 97.8% andthat the product comprised 95.7% of the E-form alcohol and 4.3% of theZ-form alcohol. High-performance liquid chromatography on opticallyactive column showed that the enantiomer ratio of the E-form alcoholwas: (+)-form, 85.0%; and (-)-form, 15.0%.

Reference Example 1

To a mixture of 8.43 g (0.04 mole) of(±)-erythro-2-amino-1-(2,4-dimethoxyphenyl)-1-propanol (erythro/threo=98.9/1.1) and 60 ml of water was added 5.21 g (0.04 mole) ofD-(-)-pantolactone, and after stirring at 80° to 90° C. for 1 hour, thereaction solution was concentrated under reduced pressure. The residueobtained was recrystallized from 50 ml of methanol-ethanol (1:4) mixtureto obtain 5.44 g of the diastereomer salt of D-(-)-pantoic acid. [α]_(D): -16.0° (c=1.0, water). This product was recrystallized once more from50 ml of ethanol to obtain 3.64 g of D-(-)-pantoic acid salt of(-)-erythro-2-amino-1-(2,4-dimethoxyphenyl)-1-propanol. [α]_(D) : -19.4°(c=1.0, water). The diastereomer salt obtained was decomposed with asolution of 1 g of potassium hydroxide in 10 ml of water and extractedwith methylene chloride to obtain 2.07 g of(-)-erythro-2-amino-1-(2,4-dimethoxyphenyl)-1-propanol(erythro/threo=99.6/0.4). m.p.: 92°- 93° C. The optical purity of thisproduct was 98.6% by high-performance liquid chromatographic analysis.By dissolving this aminoalcohol in a mixed solvent of diethyl ether andmethylene chloride and passing a hydrogen chloride gas therethrough,2.36 g of (-)-erythro-2-amino-1-(2,4-dimethoxyphenyl)-1-propanolhydrochloride was obtained. m.p.: 183°-183.5° C. (decomp.). [α]_(D) :-34.0° (c=1.0, water). The optical purity of this product was 98.6% byhigh-performance liquid chromatographic analysis.

Reference Example 2

A mixture of 14.05 g of(±)-erythro-2-amino-1-(2-methoxyphenyl)-1-propanol(erythro/threo=98.0/2.0), 10.09 g of D-(-)-pantolactone and 100 ml ofwater was heated for 1 hour with stirring and concentrated under reducedpressure. The residue obtained was recrystallized from 110 ml ofisopropanol to obtain 5.09 g of the D-(-)-pantoic acid salt of(+)-erythro-2-amino-1-(2-methoxyphenyl)-1-propanol. [α]_(D) : +22.9°(c=0.9, water). This diastereomer salt was decomposed with a solution of1.61 g of potassium hydroxide in 20 ml of water and extracted withchloroform to obtain 2.58 g of(+)-erythro-2-amino-1-(2-methoxyphenyl)-1-propanol. By dissolving thisaminoalcohol in diethyl ether-chloroform mixture and passing a hydrogenchloride gas therethrough, the hydrochloric acid salt of theaminoalcohol was formed. This salt was collected by filtration and driedto obtain 2.82 g of (+)-erythro-2-amino-1-(2-methoxyphenyl)-1-propanolhydrochloride. [α]_(D) : +26.5° (c=1.0, water). This product wasconverted to its sugar derivative (diastereomer) and analyzed byhigh-performance liquid chromatography to find that its optical puritywas 62.6%. The filtrate after recrystallization was concentrated underreduced pressure to obtain 20.28 g of the D-(-)-pantoic acid salt of(-)-erythro-2-amino-1-(2-methoxyphenyl)-1-propanol. [α]_(D) : +1.29°(c=1.0, water). This product was recrystallized from isopropanol, andafter filtration, the filtrate obtained was concentrated under reducedpressure, decomposed with a solution of 3.76 g of potassium hydroxide in47 ml of water and extracted with chloroform to obtain 6.79 g of(-)-erythro-2-amino-1-(2-methoxyphenyl)-1-propanol. This aminoalcoholwas converted to its sugar derivative (diastereomer) and analyzed byhigh-performance liquid chromatography to find that its optical puritywas 44.6%. By dissolving this aminoalcohol in diethyl ether-chloroformmixture and passing a hydrogen chloride gas therethrough,(-)-erythro-2-amino-1-(2-methoxyphenyl)-1-propanol hydrochloride wasobtained. After recrystallizing this hydrochloride three times fromethanol, 1.75 g of (-)-erythro-2-amino-1-(2-methoxyphenyl)-1-propanolhydrochloride was obtained from the filtrate. [α]_(D) : -37.7° (c=1.0,water). The optical purity of this product was 98.0% by high-performanceliquid chromatographic analysis.

Reference Example 3

On adding a hot solution of 20.5 g (0.0918 mole) of(±)-erythro-2-amino-1-(2,5-diethoxyphenyl)-1-propanol(erythro/threo=98.4/1.6) in 40 ml of methanol to a hot solution of 13.78g (0.0918 mole) of L-(+)-tartaric acid in 50 ml of methanol, a crystalwas deposited. This crystal was re-dissolved in the solution byadditionally adding 140 ml of methanol, and after allowing to cool, thedeposited crystal was collected by filtration. The yield of the crystalwas 12.43 g. [α]_(D) : +28.0° (c=1.0, water). This crystal was furtherrecrystallized from 150 ml of methanol to obtain 7.44 g of theL-(+)-tartaric acid salt of(+)-erythro-2-amino-1-(2,5-diethoxyphenyl)-1-propanol. [α]_(D) : +31.8°(c=1.0, water). This salt was decomposed with a 10% aqueous sodiumhydroxide solution and extracted with methylene chloride to obtain 4.75g of (+)-erythro-2-amino-1-(2,5-diethoxyphenyl)-1-propanol(erythro/threo=100/0). By dissolving this product in diethyl ether andpassing a hydrogen chloride gas therethrough, 5.40 g of(+)-erythro-2-amino-1-(2,5-diethoxyphenyl)-1-propanol hydrochloride wasobtained. m.p.: 136.5°-138.5° C. [α]_(D) : +29.1° (c=1.0, water). Theoptical purity of this product was 99.0% or more by high-performanceliquid chromatographic analysis.

Reference Example 4

A hot solution of 11.19 g of(±)-erythro-2-amino-1-(2-ethoxyphenyl)-1-propanol (content of theerythro-form, 99% or more) in 15 ml of methanol was added to a hotsolution of 8.60 g of L-(+)-tartaric acid in 20 ml of methanol, and theresulting solution was allowed to cool. The deposited crystal wascollected by filtration to obtain 10.44 g of the L-(+)-tartaric acidsalt of (-)-erythro-2-amino-1-(2-ethoxyphenyl)-1-propanol. [α]_(D) :+6.3° (c=1.0, water). This salt was recrystallized from methanol toobtain 4.50 g of a crystal. [α]_(D) : -8.4° (c=1.0, water). This crystalwas decomposed with a 20% aqueous sodium hydroxide solution andextracted with chloroform to obtain 2.79 g of(-)-erythro-2-amino-1-(2-ethoxyphenyl)-1-propanol. [α]_(D) : -16.4°(c=1.0, CHCl₃). This aminoalcohol was converted to its sugar derivative(diastereomer) and analyzed by high-performance liquid chromatography tofind that its optical purity was 63.2%. By dissolving this aminoalcoholin diethyl ether-chloroform mixture and passing a hydrogen chloride gastherethrough, 3.18 g of(-)-erythro-2-amino-1-(2-ethoxyphenyl)-1-propanol hydrochloride wasobtained. Recrystallization of this product from isopropanol wasrepeated four times to obtain 1.02 g of a crystal. [α]_(D) : -43.6°(c=1.0, water). The optical purity of the crystal was 97.8%.

Reference Example 5

On adding a solution of 4.56 g (0.0263 mole) of N-acetyl-L-leucine and1.11 g (0.0263 mole) of 95% sodium hydroxide in 50 ml of water to asolution of 12.17 g (0.0525 mole) of(±)-erythro-2-amino-(2-methoxy-5-methylphenyl)-1-propanol hydrochloride(erythro-form, 99% or more) in 115 ml of water, a crystal was deposited.This crystal was re-dissolved in the solution by additionally adding 500ml of water, and after allowing to cool, the deposited crystal wascollected by filtration. The yield of the N-acetyl-L-leucine salt of(-)-erythro-2-amino-1-(2-methoxy-5-methylphenyl)-1-propanol was 3.63 g.[α]_(D) : -29.2° (c=1.0, water). This salt was decomposed with a 10%aqueous sodium hydroxide solution and extracted with chloroform toobtain 1.94 g of(-)-erythro-2-amino-1-(2-methoxy-5-methylphenyl)-1-propanol. [α]_(D) :-22.1° (c=1.1, CHCl₃). By dissolving this product in diethyl ether andpassing a hydrogen chloride gas therethrough, 2.13 g of(-)-erythro-2-amino-1-(2-methoxy-5-methylphenyl)-1-propanolhydrochloride was obtained. This salt was recrystallized fromisopropanol to obtain 1.65 g of the crystal. [α]_(D) : -22.2° (c=1.0,water). The optical purity of this product as sugar derivative(diastereomer) was 97.8% by high-performance liquid chromatographicanalysis.

Reference Example 6

31 Grams (0.114 mole) of 2-amino-1-(2,5-diethoxyphenyl)-1-propanonehydrochloride was dissolved in 450 ml of water, and 2.15 g (0.0568 mole)of sodium borohydride was added at 3° to 7° C. After maintaining thetemperature for 2 hours with stirring, the reaction solution wasacidified with conc. hydrochloric acid and washed with chloroform. Theaqueous layer was made alkaline with a 25% aqueous sodium hydroxidesolution and extracted with chloroform to obtain 24.1 g of(±)-erythro-2-amino-1-(2,5-diethoxyphenyl)-1-propanol(erythro/threo=93.6/6.4). This product was recrystallized from tolueneto obtain 21.0 g of a crystal (erythro/threo=98.4/1.6).

M.p., 108°-109° C.

NMR spectrum (CDCl₃): δ (ppm): 0.99(d 3H), 1.37(t 6H), 1.4-2.2(broad2H), 3.24(m H), 3.98(q 4H), 4.72(d H), 6.74(2H), 6.96(H).

Reference Example 7

20 Grams (0.0938 mole) of 2-amino-1-(2-ethoxyphenyl)-1-propanonehydrochloride was dissolved in 300 ml of water, and 1.77 g (0.0468 mole)of sodium borohydride was added at 5° to 8° C. After maintaining thetemperature for 1 hour with stirring, the reaction solution was allowedto stand overnight at room temperature. Thereafter, the reactionsolution was acidified with conc. hydrochloric acid and then madealkaline with a 25% aqueous sodium hydroxide solution. The depositedcrystal was collected by filtration, washed with water and dried toobtain 13.40 g of erythro-2-amino-1-(2-ethoxyphenyl)-1-propanol as acrystal (erythro/threo=98.4/1.6). This crystal was recrystallized fromtoluene to obtain 12.39 g of a crystal (content of the erythro-form, 99%or more).

m.p., 89°-91° C.

NMR spectrum (CDCl₃): δ (ppm): 0.99(d 3H), 1.40(t 3H), 1.6-2.4(broad2H), 3.24(m H), 3.99(q 2H), 4.76(d H), 6.7-7.04(m 2H), 7.05-7.45(m 2H).

What is claimed is:
 1. An asymmetrically modified boron hydride typecompound obtained by reacting a borane with an optically active aminoalcohol represented by the formula (I), ##STR41## wherein R₁ representsa C₁ -C₄ alkyl, phenyl, naphthyl or phenyl substituted with at least oneC₁ -C₄ alkyl or at least one C₁ -C₄ alkoxy, R₂ represents a C₁ -C₄alkyl, phenyl or alkoxycarbonyl having 2-11 carbon atoms, R₃ representshydrogen and the mark * means an asymmetric carbon, with the provisothat when R₁ represents phenyl, R₂ does not represent methyl, orreacting an acid salt of the optically active amino alcohol with a metalborohydride.
 2. A compound produced by the process of claim 1, wherein,in the above formula (I), R₁ is naphthyl, and R₂ is methyl.
 3. Acompound produced by the process of claim 1, wherein, in the aboveformula (I), R₁ is 2,4-dimethoxyphenyl, and R₂ is methyl.
 4. A compoundproduced by the process of to claim 1, wherein in the above formula (I),R₁ is 2,5-diethoxyphenyl, and R₂ is methyl.
 5. A compound produced bythe process of claim 1, wherein, in the above formula (I), R₁ is2,5-dimethoxyphenyl, and R₂ is methyl.
 6. A compound produced by theprocess of claim 1, wherein, in the above formula (I), R₁ is2-methoxyphenyl, and R₂ is methyl.
 7. A compound produced by the processof claim 1, wherein, in the above formula (I), R₁ is 2-ethoxyphenyl, andR₂ is methyl.
 8. A compound produced by the process of claim 1, wherein,in the above formula (I), R₁ is 2,5-dimethylphenyl, and R₂ is methyl. 9.A compound according to claim 1, wherein the borohydride compound is ametal borohydride selected from the group consisting of sodiumborohydride, potassium borohydride, lithium borohydride and zincborohydride.
 10. A compound according to claim 1, wherein the acid saltof the optically active amino alcohol is a salt of an acid selected fromthe group consisting of, mineral acids, carboxylic acids and organicsulfonic acids.
 11. A compound according to claim 9 wherein the molarratio of the acid salt of the optically active amino alcohol to themetal borohydride is 1:0.7 to 1:1.3, as converted to boron basis.
 12. Acompound according to claim 1, wherein the borohydride compound isborane and the molar ratio of the optically active amino alcohol to theborane is 1:0.7 to 1:1.3, as converted to boron basis.
 13. A compoundproduced by the process of claim 1, which is obtained by reacting anacid salt of the optically active amino alcohol with a metalborohydride.
 14. A compound produced by the process of claim 1, which isobtained by reacting the optically active amino alcohol with a borane.15. A compound produced by the process of claim 1, wherein R₁ representsmethyl, phenyl, naphthyl, 2-methoxyphenyl, 2-ethoxyphenyl,2,5-dimethylphenyl, 2,5-dimethoxyphenyl, 2,5-diethoxyphenyl or2,4-dimethoxyphenyl; and R₂ represents methyl, phenyl, ethoxycarbonyl(--COOC₂ H₅) or cyclohexyloxycarbonyl (--COOC₆ H₁₁).
 16. A compoundaccording to claim 14, wherein the borane is diborane,borane-tetrahydrofuran complex or borane-dimethyl sulfide complex.
 17. Acompound according to claim 14, wherein the borane isborane-tetrahydrofuran complex.
 18. A compound according to claim 13,wherein the metal borohydride is sodium borohydride.
 19. A method forproducing an asymmetrically modified borohydride type compoundcharacterized in that a borane is reacted with an optically active aminoalcohol represented by the formula (I) ##STR42## wherein R₁ represents aC₁ -C₄ alkyl, phenyl, naphthyl or phenyl substituted with at least oneC₁ -C₄ alkyl or at least one C₁ -C₄ alkoxy, R₂ represents a C₁ -C₄alkyl, phenyl or alkoxycarbonyl having 2-11 carbon atoms, R₃ representshydrogen, and the mark * means an asymmetric carbon, with the provisothat when R₁ is phenyl, R₂ is not methyl, or an acid salt of theoptically active amino alcohol is reacted with a metal borohydride. 20.A method according to claim 19, wherein, in the above formula (I), R₁ isnaphthyl, and R₂ is methyl.
 21. A method according to claim 19, wherein,in the above formula (I), R₁ is 2,5-diethoxyphenyl, and R₂ is methyl.22. A method according to claim 19, wherein, in the above formula (I),R₁ is dimethoxyphenyl, and R₂ is methyl.
 23. A method according to claim19, wherein, in the above formula (I), R₁ is 2-methoxyphenyl, and R₂ ismethyl.
 24. A method according to claim 19, wherein, in the aboveformula (I), R₁ is 2-ethoxyphenyl, and R₂ is methyl.
 25. A methodaccording to claim 19, wherein, in the above formula (I), R₁ is2,5-dimethylphenyl, and R₂ is methyl.
 26. A method according to claim19, which comprises reacting an acid salt of the optically active aminoacid with a metal borohydride.
 27. A method according to claim 26,wherein the metal borohydride is sodium borohydride, potassiumborohydride, lithium borohydride or zinc borohydride.
 28. A methodaccording to claim 26, wherein the acid is a mineral acid, carboxylicacid or organic sulfonic acid.
 29. A method according to claim 26,wherein the molar ratio of the acid salt of the optically active aminoalcohol to the metal borohydride is 1:0.7 to 1:1.3, as converted toboron basis.
 30. A method according to claim 19, which comprisesreacting the optically active alcohol with a borane.
 31. A methodaccording to claim 30, wherein the molar ratio of the optically activeamino alcohol to the borane is 1:0.7 to 1:1.3, as converted to boronbasis.
 32. A method according to claim 19, wherein R₁ represents methyl,phenyl, naphthyl, 2-methoxyphenyl, 2-ethoxyphenyl, 2,5-dimethoxyethyl or2,4-dimethoxyphenyl; and R₂ represents methyl or cyclohexyloxycarbonyl(--COOC₆ H₁₁).
 33. A method according to claim 30, wherein the borane isdiborane, borane-tetrahydrofuran complex or borane-dimethyl sulfidecomplex.
 34. A method according to claim 30, wherein the borane isborane-tetrahydrofuran complex.
 35. A method according to claim 26,wherein the metal borohydride is sodium borohydride.
 36. A methodaccording to claim 19, wherein, in the above formula (I), R₁ is2,4-dimethoxyphenyl and R₂ is methyl.